Catalyst- and Reagent-Free Formal Aza-Wacker Cyclizations Enabled by Continuous-Flow Electrochemistry

Article abstract of DOI:10.1002/anie.202101835

The development of efficient and sustainable methods to access saturated N-heterocycles is of great importance because of the prevalence of these structures in natural products and bioactive compounds. Pd-catalyzed aza-Wacker type cyclization is a powerful method and provides access to N-heterocycles bearing an alkene moiety available for further synthetic manipulations from readily available materials. Herein we disclose a catalyst- and reagent-free formal aza-Wacker type cyclization reaction for the synthesis of functionalized saturated N-heterocycles. Key to the success is to conduct the reactions in a continuous-flow electrochemical reactor without adding supporting electrolyte or additives. The reactions are characterized by broad tolerance of di-, tri- and tetrasubstituted alkenes.

Full text of DOI:10.1002/anie.202101835

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11237–11241
International Edition: doi.org/10.1002/anie.202101835
German Edition: doi.org/10.1002/ange.202101835
Electrochemistry
Hot Paper
Catalyst- and Reagent-Free Formal Aza-Wacker Cyclizations Enabled
by Continuous-Flow Electrochemistry
Chong Huang, Zhao-Yu Li, Jinshuai Song, and Hai-Chao Xu*
Abstract: The development of efficient and sustainable
methods to access saturated N-heterocycles is of great impor-
tance because of the prevalence of these structures in natural
products and bioactive compounds. Pd-catalyzed aza-Wacker
type cyclization is a powerful method and provides access to N-
heterocycles bearing an alkene moiety available for further
synthetic manipulations from readily available materials.
Herein we disclose a catalyst- and reagent-free formal aza-
Wacker type cyclization reaction for the synthesis of function-
alized saturated N-heterocycles. Key to the success is to conduct
the reactions in a continuous-flow electrochemical reactor
without adding supporting electrolyte or additives. The reac-
tions are characterized by broad tolerance of di-, tri- and
tetrasubstituted alkenes.
S
aturated N-heterocycles such as pyrrolidines are prevalent
structural motifs in natural products and bioactive com-
pounds.[1] Furthermore, it has been shown that increasing
saturation in small molecules correlates strongly to their
clinical success.[2] These features of saturated N-heterocycles
have prompted intense interests in their preparation. Among
various methods for the construction of these important
structures, Pd-catalyzed cyclization of alkenes bearing teth-
ered amine nucleophiles, which is often referred to as aza-
Wacker cyclization, is a rather powerful approach as it
provides N-heterocycles bearing an alkenyl moiety available
for further synthetic manipulations (Scheme 1a).[3] These
reactions, which initially require stoichiometric PdII, are now
commonly achieved with catalytic Pd using molecular oxygen
as the terminal oxidant.[4] The aza-Wacker cyclization pro-
Scheme 1. Aza-Wacker-type cyclization reactions.
À
ceeds through aminopalladation to forge the C N bond. Since
this organometallic step is sensitive to the steric properties of
the olefinic moiety, multiple substituted alkenes remain
challenging substrates.[4h] Large-scale applications of these
reactions would benefit from conditions that are free of noble
metals[5] and oxidants,[6] which leads to safer production with
reduced cost and environmental impact.
Nitrogen centered radicals (NCRs) are attractive reactive
intermediate for the synthesis of N-heterocycles and have
been attracting increasing interest.[7] While these open-shell
species are traditionally produced through cleavage of a N-
heteroatom bond,[8] generation directly from N-H precursors
under chemical,[9] photochemical[10] and electrochemical[11]
conditions have been reported. Relevant to this work,
Moeller and co-workers reported electrooxidative intramo-
lecular coupling of sulfonamides with electron-rich alkenes
via radical cyclization.[11]
[*] C. Huang, Z.-Y. Li, Prof. Dr. H.-C. Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces
Key Laboratory of Chemical Biology of Fujian Province, and
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen 361005 (China)
E-mail: haichao.xu@xmu.edu.cn
We[12] and the Hu group[13] have developed electrochem-
ical methods[14] to achieve formal aza-Wacker cyclizations of
alkene-tethered anilides also via NCR cyclizations (Sche-
me 1b). Although these methods are free of chemical
oxidants and employ a base-metal catalyst such as Cu or no
catalyst at all, they require anilide substrates, which are
relatively easy to oxidize, and are not applicable to the direct
synthesis of saturated N-heterocycles. In addition, supporting
Dr. J. Song
Green Catalysis Center, and College of Chemistry
Zhengzhou University, Zhengzhou 450001 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101835.
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salts and acidic or basic additives are employed in these
electrolytic reactions with batch reactors. Compared with
traditional electrosynthesis in batch reactors, electrolysis
using continuous-flow electrochemical cells is advantageous
due to the reduction in use of supporting electrolyte, easy
scale-up, short residence time, and efficient mass transfer.[15]
These salient features render continuous-flow electrochemis-
try a highly attractive and enabling tool for developing
sustainable synthetic methodologies.[16]
any additive or supporting electrolyte through the cell at
0.2 mLminÀ1 afforded the desired pyrroline 2 in 52% yield
(entry 1). Interestingly, the inclusion of supporting electrolyte
such as Et4NPF6 (0.1 equiv) or nBu4NBF4 (0.1 equiv) in the
reaction mixture resulted in drastic reduction in the yield of 2
to around 10% due to low conversion (entries 2 and 3). The
addition of basic salts such as nBu4NOAc (entry 4) and
NaOCH(CF3)2 (entry 5) failed to boost the yield of 2. The use
of the mixed solvent mixture was critical for success as
omitting either one led to either low yield of 2 (entry 6) or
complete failure (entry 7). Replacing DMA with acetonitrile
(entry 8) or HFIP with other alcohols such as TFE (entry 9)
or MeOH (entry 10) all resulted in diminished yield. While Ni
cathode was as effective as Pt (entry 11), stainless steel
(entry 12) or graphite (entry 13) were less effective. The
interelectrode distance could be reduced to 125 mm or
increased to 500 mm without affecting the reaction efficiency
(entry 14). However, conducting the reaction in batch com-
pletely abolished product formation with most of 1 left
unreacted (entry 15). In this case, a supporting electrolyte was
needed to increase conductivity.
We next evaluated the substrate scope of the electro-
oxidative amination reaction (Scheme 2). The reaction was
compatible with various di- (3–19), tri- (20–31) and tetrasub-
stituted (32, 33) alkenes. Unlike the transition-metal cata-
lyzed aza-Wacker cyclizations, our electrochemical reactions
were generally more efficient with tri- and tetrasubstituted
alkenes than disubstituted alkenes due to the electrophilic
nature of the sulfonamidyl radical and the more facile alkene
regeneration from the more substituted olefins. 1,2-Disubsti-
tuted (E)-alkenes bearing at the allylic position 18 (3), 28 (4–
6), or 38 (7) alkyl substituent, phenyl (8) or thiophene (9)
cyclized to give pyrrolidines with good to excellent diaste-
reoselectivity favoring the trans-isomer. Introduction of an
OTBDPS (9) or OAc group (11) at this position resulted in
low diastereoselectivity. However, the stereoselectivity can be
increased by switching to a (Z)-isomer of the alkene substrate
as demonstrated for the synthesis of 11 with exclusive trans-
isomer.[18] An a-branched sulfonamide reacted smoothly but
with a poor diastereomeric ratio (d.r.) of 1.3:1 (12).
The arylsulfonyl moiety also tolerated variation. Benze-
nesulfonyl groups bearing at the 4-position a H (34), OMe
(35), Br (36), CF3 (37), esters (39, 40), isoxazole (41) or
pyrazole (42) were all tolerated. Installation of a highly
electron-withdrawing nitro group (38) at this position resulted
in reaction failure possibly because of the reductive decom-
position of the substrate at the cathode. The Ts group could
be replaced with heteroarenesulfonyl groups such as 2-
pyridinesulfonyl (43) and 2-thiophenesulfonyl (44). N-tosyla-
mides were also viable substrates for the cyclization to form
functionalized g-lactams (45, 46). Methanesufonamide (47)
and trifluoromethanesulfonamide (48) were also suitable
substrates but less efficient than the arylsulfonamides. The
less acidic Boc-amide (49) and benzamide (50) failed to
provide any desired vinyl heterocycles. The electrochemical
method could also be used for the preparation of function-
alized piperidines as demonstrated by the diastereoselective
synthesis of 51.
À
With our continued interest in electrochemical C N bond
forming reactions,[17] we report herein catalyst-, reagent-, and
additive-free, formal aza-Wacker cyclizations for the syn-
thesis of saturated N-heterocycles (Scheme 1c). Key to the
success is to carry out the reactions in an electrochemical
continuous-flow reactor under electrolyte-free conditions as
the presence of inert supporting salts shuts down the
cyclizations. This method is compatible with di-, tri- and
tetrasubstituted alkenes thanks to the radical mechanism of
À
the C N bond formation.
Sulfonamide 1 bearing a disubstituted internal alkene was
chosen as a model substrate to optimize the electrolysis
conditions (Table 1). This type of alkenes failed in our
previous work on the electrochemical cyclization of anilides
because of the difficult in oxidizing secondary C-radicals.[7]
Under the optimal conditions, the flow reactor contained
a graphite anode, a Pt cathode, and an FEP spacer with
a thickness of 250 mm and operated at a constant current of
45 mA. Pumping a solution of 1 in DMA/HFIP (5:1) without
Table 1: Optimization of reaction conditions.[a]
Entry
Deviation from standard conditions
Yield [%][b]
1
None
52[c]
2
3
4
5
Addition of Et4NPF6 (0.1 equiv)
Addition of nBu4NBF4 (0.1 equiv)
Addition of nBu4NOAc (0.1 equiv)
Addition of NaOCH(CF3)2 (0.5 equiv)
HFIP as solvent
9 (80)
12 (80)
51
43 (19)
12
0 (80)
11
46
35 (5)
52
46
35 (26)
50–51
6
7[d]
8
DMA as solvent
MeCN/HFIP (5:1) as solvent
DMA/TFE (5:1) as solvent
DMA/MeOH (5:1) as solvent
Ni as cathode
Stainless steel as cathode
Graphite as cathode
9
10[d]
11
12
13
14
Interelectrode distance=125 mm or 500 mm
15
0 (86)
[a] Electrolysis conditions: graphite anode, Pt cathode, electrode surface
(10 cm2), interelectrode distance=250 mm, 1 (0.3 mmol), solvent
(9 mL), tr =75 s (calculated), 45 min (4.2 FmolÀ1). [b] Determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
Recovered 1 is given in brackets. [c] Yield of isolated 2. [d] 0.1 equiv of
nBu4NBF4 was added to reduce cell potential. DMA, N,N-dimethylace-
tamide; HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol; TFE, 2,2,2-trifluoroe-
thanol.
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Scheme 2. Reaction scope. [a] (E)-alkene as substrate. [b] (Z)-alkene as substrate. [c] Nickel as cathode. Ms=methanesulfonyl; Tf=trifluorome-
thanesulfonyl.
The scale up of the electrosynthesis was accomplished
through numbering up using four parallel reactors (Figure 1).
A solution of 12.9 g of 52 in DMA/HFIP was pumped through
the reactors in 16.7 h to afford 27 in 87% yield (11.1 g,
0.66 ghÀ1). Importantly, although the electric current and flow
of each reactor were increased by 50% from the standard
conditions to increase productivity, the reaction efficiency
remained unaffected, showcasing the robustness of the
method. The scale up can also be achieved with Ni cathodes
to produce 11.5 g of 27 (88% yield) in 17 h. In this case, the
addition of 5 mol% of nBu4NOAc in the reaction mixture was
helpful in stabilizing the system for long time operation.
We next probed the reaction mechanism of the electro-
chemical cyclization reactions (Scheme 3). Subjecting the
cyclopropane substrate 53 into the electrolysis afforded the
cyclization-ring opening product 54 in 15% yield (Sche-
me 3a). This product was most likely formed through
sequential cyclization to form C-radical 55, SET oxidation
to carbocation 56, reaction with DMA to give iminium 57, and
hydrolysis during workup. The alternative pathway to 57 that
involved ring-opening of radical 55 followed by oxidation and
solvent trapping was considered less likely due to the
difficulty in the oxidation of a primary C-radical to a highly
unstable primary carbocation. In any case, these results
suggested that the electrochemical cyclization formed a C-
Figure 1. Reaction scale-up employing four parallel reactors. Reaction
conditions: graphite anode, Pt cathode, DMA/HFIP (5:1), cur-
rent=60 mA (for each reactor), 0.3 mLminÀ1 (for each reactor), rt,
16.7 h. [a] The electrolysis was conducted with Ni cathodes in the
presence of nBu4NOAc (5 mol%) for 17 h.
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However, the latter route is unlikely under the standard
reaction conditions considering that amides such as 59–62,
which are more nucleophilic on the carbonyl oxygen than the
amidyl nitrogen, all undergo N-cyclization instead of O-
cyclization (Scheme 3b). In addition, the retain of an alkene
in the final product also discouraged such a mechanism. The
reactions of amides 58–62 also suggested that the N-radicals
were generated via proton-coupled electron-transfer
(PCET)[19] because the amides with lower oxidation poten-
tials reacted less efficiently and the reaction efficiency
increased with increasing acidity of the amide moiety
(Scheme 3b). This mechanism reduced the potential needed
for substrate oxidation and allowed the reaction to proceed in
DMA, a solvent with relatively low anodic decomposition
potential. In fact, cyclic voltammetry studies showed that the
oxidation of the sulfonamide substrates such as 1 via sequen-
tial electron/proton loss was difficult in DMA because the
solvent was oxidized preferentially (Scheme 3c).
A possible mechanism for the electrochemical formal aza-
Wacker cyclization is shown in Scheme 3d. Anodic oxidation
of sulfonamide 1 with hexafluoroisopropoxide as a base via
PCET produces N-radical 67, which cyclizes to furnish C-
radical 68. Single-electron transfer (SET) oxidation of 68
generates carbocation 69, which cyclizes to give bicyclic
cation 70 a more stable cationic species found by computa-
tional geometry optimization of 69.[20] 70 then undergoes E2
elimination of Hb to afford the final alkene 2 as the kinetic
product. Elimination of proton Ha would afford a thermody-
namic product but kinetically less favorable due to the
involvement of a 5-endo-trig type transition state. Protons are
reduced at the cathode to generate H2.
During the electrolysis in the absence of supporting
electrolyte, the positively charged anode and negatively
charged cathode induces dissociation of HFIP to generate
hexafluoroisopropoxide and proton to counterbalance their
charge.[21] As a result, high local concentration of hexafluor-
oisopropoxide is present in the electric double layer on the
anode to help the PCET process. When a supporting salt is
added, the double layer consists inert ions and there is not
enough hexafluoroisopropoxide to assist the substrate oxida-
tion. Under these conditions, solvent DMA discharges
preferentially leading to low conversion.
In summary, we have developed an electrochemical
method to achieve aza-Wacker-type cyclization reactions for
the synthesis of saturated N-heterocycles without need for
any catalyst, additives or supporting electrolyte. The mild and
simple reaction conditions coupled with its broad compati-
bility of with alkene substitution patterns make this method
attractive for medicinal and industrial applications. This work
clearly demonstrates that continuous-flow electrochemistry
holds great promise in developing powerful and sustainable
synthetic methodologies.
Scheme 3. Mechanistic studies and proposal.
radical. The C-radical might arise from the reaction of
a sulfonamidyl radical with the tethered alkene, or intra-
molecular trapping of an alkene radical cation with the
sulfonamide nucleophile, depending on the site of the initial
electron loss.
Acknowledgements
The authors acknowledge the financial support of this
research
from
NSFC
(21971213),
MOST
(2016YFA0204100), and Fundamental Research Funds for
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Chen, H.-M. Guo, Q.-Q. Zhao, J.-R. Chen, W.-J. Xiao, Chem.
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Keywords: continuous flow · cyclization · electrochemistry ·
heterocycles · radical reactions
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Manuscript received: February 5, 2021
Revised manuscript received: February 22, 2021
Accepted manuscript online: March 5, 2021
Version of record online: April 7, 2021
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